Crassulacean acid metabolism (CAM), a special mode of photosynthesis, features nocturnal CO2 uptake, which facilitates increased water-use efficiency (WUE) and enables CAM plants to inhabit water-limited environments such as semi-arid deserts or seasonally dry rain forests. Human population growth in combination with global climate change now challenges agricultural production systems to increase food, feed, forage, fiber and fuel production by expanding into semi-arid, abandoned, marginal, or degraded agricultural lands. Such sustainable dryland production increases are envisioned by increased reliance on highly water-use efficient CAM crop species, such as Agave and Opuntia. Thus, major research efforts are now underway to provide detailed assessments of the productivity of major CAM crop species and to harness the WUE of CAM by engineering this pathway into existing food and bioenergy crops. The gains in understanding CAM photosynthesis through an expanded research effort have potential for high returns on investment in the foreseeable future. To help realize this potential, it is necessary to address important scientific questions related to genomic features, regulatory mechanisms, CAM evolution, CAM-into-C3 engineering, and sustainable CAM crop production. Answering these questions requires collaborative efforts to build infrastructure for CAM model systems, field trials, mutant collections, and data management.